Cystathionine beta-synthase deficient homocystinuria (CBSDH) is a rare inherited disorder that is clinically silent at birth but with significant morbidity and mortality over time. It is increasngly recognized since the introduction of expanded newborn screening. Affected individuals exhibit increased blood clotting, lens problems, osteoporosis, skeletal abnormalities, and intellectual disability. Although current treatments improve outcome, limitations and adverse side effects exist, and treatment compliance is poor. Consequently, a need for novel therapeutic strategies exists. Data from research on a genetically engineered mouse model of CBSDH indicates that oxidative stress and systemic chronic inflammation play a critical primary initiating role in the pathogenesis of this disorder and that supplementation with taurine mitigates these effects and improves function including normalization of coagulation, improved cognition, and improved bone mineral density. In this application, the investigators propose a short-term, single dose, exploratory Phase 1/2 study to identify which parameters are likely to respond to taurine treatment, in addition to safet and pharmacokinetic data. This multi-center, open label study will include 12 patients between ages 8 to 50 years old with CBSDH who will be given taurine 75 mg/kg (maximum 5 grams) twice a day for a total dose of 150 mg/kg/day (maximum 10 grams per day) for 41/2 days. For safety reasons only, the first two patients will be treated with a dose of 25 mg/kg/dose (maximum 1.5 g) twice daily. After review of safety parameters, the dose will then be increased to the planned dose of 75 mg/kg/dose (maximum 5 g) twice daily. During the study, the standard treatment will not be altered. Patients will continue their existing treatment of dietary restrictin, if present, and betaine therapy, and any other prescribed therapies. In specific aim 1 of the proposal, the investigators will perform a Phase 1 study designed to document the safety and pharmacokinetic characteristics of taurine treatment specifically in CBSDH patients. In specific aim 2, the investigators will perform a Phase 2 study to investigate the plasma levels of oxidative stress and inflammation in CBSDH in the presence and absence of taurine treatment. Oxidative stress and inflammation will be assessed by measurement of plasma levels of thiobarbituric acid reactive substances (TBARS) and tumor necrosis factor alpha (TNF-alpha), chosen based on the results of a preliminary study. In specific aim 3, the investigators will conduct an exploratory systematic study designed to identify additional markers of oxidative stress and inflammation in CBSDH with a view towards assessing the therapeutic effects of taurine. Additionally, they will investigate the relevance of these biomarkers to pathogenesis by studies of plasma methionine cycle metabolites, platelet aggregation, endothelial dysfunction, and bone mineral density.

R01FD003907

2013-09-16

2016-06-30